Summary
Colorectal carcinoma is one of the most common cancers in Western countries (yearly incidence rate of 1: 3000), and represents, after lung cancer, the second leading cause of deaths due to cancer. During the past decades, knowledge about this carcinoma has considerably increased, but little progress has been made in improvement in patient survival. At least 40% of patients with colorectal cancer will have metastases sometime during the course of their illness.
In colon cancer, the first therapeutic approach is surgery, but the important role of adjuvant chemotherapy in these patients, in terms of disease-free survival and overall survival benefit, is now well established. Until today, standard therapy was represented by fluorouracil plus levamisole and/or calcium folinate (folinic acid). Other strategies are represented by monoclonal antibodies (mAb), which improve survival, (with a decrease in mortality by 32%), and by portal vein fluorouracil, alone or in combination with systemic therapy. In rectal cancer, the best results have been obtained with a combination of radiotherapy and chemotherapy.
In advanced colorectal cancer, a standard treatment has not yet been established. This disease is usually considered as poorly chemosensitive and for more than 30 years fluorouracil has been the standard drug. Tumour response rates (partial + complete) for patients treated with bolus intravenous fluorouracil are 10 to 15%, with a median survival about 1 year.
Many attempts have been made to improve these results. Biochemical modulation of fluorouracil is one of the most interesting strategies developed in the last few years in an attempt to increase the therapeutic index of this compound. Another way has been to administer fluorouracil by continuous infusion. Further innovative compounds such as irinotecan and raltitrexed are now being evaluated in clinical trials. Preliminary data from phase II and III studies have provided encouraging results on the use of these new drugs. In metastatic disease confined to the liver, the possibility of locoregional therapy through implantable pumps should be taken into consideration.
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References
Boring CC, Squires TS, Tong T. Cancer statistics. Cancer J Clin 1993; 43: 7–10
Astler VA, Coller FA. The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg 1954; 139: 846–52
Gastrointestinal Tumor Study Group. Adjuvant therapy of colon cancer: results of a prospectively randomized trial. N Engl J Med 1984; 310: 737–41
Scivetti P, Riccardi A, Marsano B, et al. Flow cytometric DNA index in the prognosis of colorectal cancer. Cancer 1991; 67: 1921–7
Moertel CG, O’Fallon JR, Go VL, et al. The preoperative carcinoembryonic antigen test in the diagnosis, staging, and prognosis of colorectal cancer. Cancer 1986; 58: 603–6
Wolmark N, Fisher B, Wieand HS. The prognostic value of the modifications of the Dukes’ C class of colorectal cancer. Ann Surg 1986; 203: 115–22
Buyse M, Zeleniuch-Jacquotte A, Chalmers T. Adjuvant therapy of colorectal cancer: why we still don’t know. JAMA 1988; 259: 3571–8
Gray R, James R, Mossman J, Stenning S. AXIS — a suitable case for treatment. Br J Cancer 1991; 63: 851–5
Arnaud JP, Buyse M, Nordlinger B, et al. Adjuvant therapy of poor prognosis colon cancer with levamisole: results of an EORTC double-blind randomized clinical trial. Br J Surg 1989; 76: 284–9
Laurie JA, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol 1989; 7: 1447–56
Moertel CG, Fleming TR, MacDonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322: 352–8
NIH Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990: 264: 1440–50
Zalcberg JR, Siderov J, Simes J. The role of 5-fluorouracil dose in adjuvant therapy of colorectal cancer. Ann Oncol 1996; 7: 41–6
Labianca R, Marsoni S, Pancera G, et al. International Multicentre Pooled Analyses of Colon Cancer Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995; 345: 939–44
Wolmark N, Rockette H, Mamounas EP, et al. The relative efficacy of 5-FU + Leucovorin (FU-LV), 5-FU + Levamisole (FU-LEV), and 5-FU + Leucovorin + Levamisole (FU-LV-LEV) in patients with Dukes’ B and C carcinoma of the colon: first report of NSABP-C-04 [abstract]. Proceedings of American Society of Clinical Oncology; 1996 May 18–21: Philadelphia; 15: 460
Haller DG, Catalano PJ, Macdonald JS, et al. Fluorouracil (FU), Leucovorin (LV) and Levamisole (LEV) adjuvant therapy for colon cancer: preliminary results of INT-0089 [abstract]. Proceedings of American Society of Clinical Oncology; 1996 May 18–21: Philadelphia; 15: 486
Matsuda T, Yasutomi M, Kikuchi K, et al. Cooperative study of surgical adjuvant chemotherapy for colorectal cancer (third report): five year results. Cooperative Study Group of Surgical Adjuvant Chemotherapy for Colorectal Cancer in Japan. Jap J Cancer Chemother 1991; 18(3): 416–9
Takashima S, Tomita F, Saito H, et al. Clinical effect of postoperative adjuvant chemotherapy for advanced colorectal cancer-comparisons between tegafur (FT) and UFT. Jpn J Cancer Chemother 1991; 18: 2315–24
Riethmueller G, Johnson JP. Monoclonal antibodies in the detection and therapy of micrometastases of epithelial cancers. Curr Opin Immunol 1992; 4: 647–55
Riethmueller G, Schneider-Gaedicke E, Johnson JP. Monoclonal antibodies in cancer therapy. Curr Opin Immunol 1993; 5: 732–9
Riethmueller G, Schneider-Gaedicke E, Schlimok G, et al. Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes’ C colorectal carcinoma. Lancet 1994; 343: 1177–83
Riethmueller G, Holz E, Schlimok G, et al. Monoclonal antibody (MAB) adjuvant therapy of Dukes C colorectal carcinoma: 7-year update of a prospective randomized trial [abstract]. Proceedings of American Society of Clinical Oncology; 1996 May 18–21: Philadelphia; 15: 1385
Hoover HC, Brandhorst JS, Peters LC, et al. Adjuvant active specific immunotherapy for human colorectal cancer: 6,5-year median follow-up of a phase III prospectively randomized trial. J Clin Oncol 1993; 11: 390–9
Vermorken JB, Claessen AME, Gall HE, et al. Randomized phase III trial of active specific immunotherapy (ASI) versus control in patients with Dukes’ B2, B3 or C colon cancer [abstract]. Proceedings of American Society of Clinical Oncology; 1996 May 18–21: Philadelphia; 15: 444
Copeland EM, Miller LD, Jones RS, et al. Prognostic factors in carcinoma of the colon and rectum. Am J Surg 1968; 116: 875–81
Pestana C, Reitemeier RJ, Moertel CG, et al. The natural history of carcinoma of the colon and rectum. Am J Surg 1964; 108: 826–9
Wolmark N, Rockette H, Wickerham DL, et al. Adjuvant therapy of Dukes’ A, B, and C adenocarcinoma of the colon with portal-vein fluorouracil hepatic infusion: Preliminary results of national surgical adjuvant breast and bowel project protocol C-02. J Clin Oncol 1990; 8: 1466–75
Piedbois P, Buyse M, Gray R, et al. Portal vein infusion is an effective adjuvant treatment for patients with colorectal cancer [abstract]. Proceedings of American Society of Clinical Oncology; 1995 May 20–23: Los Angeles; 14: 444
Witzig TE, Loprinzi CL, Gonchoroff NJ, et al. DNA ploidy and cell kinetic measurements as predictors of recurrence and survival in stage B2 and C adenocarcinoma. Cancer 1991; 68: 879–8
Moertel CG, Fleming TR, MacDonald JS, et al. Intergroup study of fluorouracil plus Levamisole as adjuvant therapy for study II/Dukes B2 colon cancer. J Clin Oncol 1995; 13: 2936–43
Mamounas EP, Rockette H, Jones J, et al. Comparative efficacy of adjuvant chemotherapy in patients with Dukes’ B vs Dukes’ C colon cancer: results from four NSABP adjuvant studies (C-01, C-02, C-03, C-04) [abstract]. Proceedings of American Society of Clinical Oncology; 1996 May 17–21: Philadelphia; 15: 461
O’Connell MJ, Laurie JA, Shepherd L, et al. A prospective evaluatin of chemotherapy duration and regimen as surgical adjuvant treatment for high risk colon cancer: a collaborative trial of the National Cancer Institute of Canada clinical trials. [abstract] Proceedings of American Society of Clinical Oncology; 1996 May 18–21: Philadelphia; 15: 478
Minsky BD. Preoperative combined modality treatment for rectal cancer. Oncology 1994; 8: 53–68
Dahl O, Horn A, Morild I, et al. Low-dose pre-operative radiation postpones recurrences in operable rectal cancer. Cancer 1990; 66: 2286–92
Stockholm Rectal Cancer Study Group. Preoperative short-term radiation therapy in operable rectal carcinoma. A prospective randomized trial. Cancer 1990; 66: 49–55
Gerard A, Buyse M, Nordlinger B, et al. Preoperative radiotherapy as adjuvant treatment in rectal cancer. Final results of randomized study of the EORTC. Ann Surg 1988; 606–14
Gastrointestinal Tumor Study Group. Survival after postoperative combination treatment of rectal cancer. N Engl J Med 1986; 312: 1465
Treurniet-Donker AD, van Putten WLJ, Weroldsma JGJ, et al. Postoperative radiation therapy for rectal cancer. Cancer 1991; 67: 2042–8
Fisher B, Wolmark N, Rockette H, et al. Postoperative adjuvant chemotherapy or radiation therapy for rectal cancer: results from NSABP protocol R-01. J Natl Cancer Inst 1988; 80: 21–9
Frykholm GJ, Glimelius B, Pahlman L. Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and evaluation of late secondary effects. Dis Colon Rectum 1993; 66: 49–55
Second report on an MRC Working Party. The evaluation of low-dose pre-operative X-ray therapy in the management of operable rectal cancer: results of a randomly controlled trial. Br J Surg 1984; 71: 21–30
Gunderson LL, Grohen AM, Dosoretz DE, et al. Residual unresectable or recurring colorectal cancer: external beam irradiation and intraoperative electron beam boost +/− resection. Int J Radiat Oncol Biol Phys 1983; 9: 1597–1605
Suzuki K, Gunderson LL, Devine RM, et al. Intraoperative irradiation following palliative surgery for locally recurrent rectal cancer. Cancer 1995; 75: 939–52
Thomas PRM, Lindblad AS. Adjuvant postoperative radiotherapy and chemotherapy in rectal carcinoma: a review of the Gastrointestinal Tumor Study Group experience. Radiother Oncol 1988; 13: 245–52
Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324: 709–15
O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994; 331: 502–7
Cass AW, Million RR, Pfaff WW. Patterns of recurrence following surgery alone for adenocarcinoma of the colon and rectum. Cancer 1976; 37: 2861–5
Seifert P, Baker LH, Reed MD, et al. Comparison of continuously infused 5-fluorouracil with bolus injection in treatment of patients with colorectal adenocarcinoma. Cancer 1975; 36: 123–8
Rougier P, Paillot B, Lapplanche A, et al. End result of multi-center randomized trial comparing 5FU in continuous systemic infusion to bolus administration in measurable metastatic colorectal cancer [abstract]. Proceedings of the American Society of Clinical Oncology; 1992 May 17–19: San Diego; 11: 465
Weinerman B, Shah A, Fields A, et al. Systemic infusion versus bolus chemotherapy in measurable colorectal cancer. Am J Clin Oncol 1992; 15: 518–23
Lokich JJ, Ahlgren JD, Gullo JJ, et al. Aprospective randomized comparison of continuous infusion fluorouracil with conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program study. J Clin Oncol 1989; 7: 425–32
Hansen R, Ryan L, Anderson T, et al. A phase III trial of bolus 5FU versus protracted infusion 5FU +/− cisplatin in metastatic colorectal cancer. An Eastern Cooperative Oncology Group study (EST 2286) [abstract]. Proceeding of American Society of Clinical Oncology, 1992 May 17–19, San Diego; 11: 499
Leichman CG, Fleming TR, Muggia M, et al. Fluorouracil (5FU) schedules and modulation in advanced colorectal cancer (CRC). A Southwest Oncology Group (SWOG) screening trial [abstract]. Proceedings of the American Society of Clinical Oncology 1993 May 16–18: Orlando, Florida; 12: 583
Machover D, Goldschmid E, Chollet P. Treatment of advanced colorectal and gastric adenocarcinomas with 5 -fluorouracil and high-dose folinic acid. J. Clin Oncol 1986; 4: 685–96
Buroker TR, O’Connell MJ, Wieand HS, et al. Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 1994; 12: 14–20
Valsecchi R, Labianca R, Cascinu S, et al. High dose (HD) versus low dose (LD) L-Leucovorin (LLV)as a modulator of 5-days 5-fluorouracil (5FU) in advanced colorectal cancer (ACC): a ‘GISCAD’ phase III study [abstract]. Proceedings of American Society of Clinical Oncology, 1995 May 20–23: Los Angeles; 14: 457
Jaeger J, Heike M, Bernhard H, et al. Weekly high-dose Leucovorin versus low-dose Leucovorin combined with Fluorouracil an advanced colorectal cancer: results of a randomized multicentric trial. J Clin Oncol 1996; 14:8, 2274–9
Advanced Colorectal Cancer Meta-Analysis Project. Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. J Clin Oncol 1994; 12: 960–9
Nobile MT, Vidili MG, Sobrero A, et al. 5-fluorouracil alone or combined with high-dose folinic acid in advanced colorectal cancer patients [abstract]. Proceedings of American Society of Clinical Oncology, 1988 may 22–24: New Orleans; 7: 371
Petrelli N, Douglass HO, Herrera, et al. The modulation of fluorouracil with leucovorin in metastatic colorectal cancer: A prospective randomized phase III trial. J Clin Oncol 1989; 7: 1419–26
Petrelli N, Herrera L, Rustum Y, et al. A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 1987; 5: 1559–65
Valone FH, Friedman MA, Wittlinger PS, et al. Treatment of patients with advanced colorectal cancer with fluorouracil alone, high dose leucovorin plus fluorouracil, or sequential, methotrexate, fluorouracil and leucovorin: a randomized trial of the Northern California Oncology Group. J Clin Oncol 1989; 7: 1427–36
Di Costanzo F, Bartolucci R, Sofra M, et al. 5-fluorouracil alone vs high dose folinic acid and 5-FU in advanced colorectal cancer. A randomized tril of the Italian Oncology Group for Clinical Research (GOIRC) [abstract]. Proceedings of American of Society of Clinical Oncology; 1989 May 21–23: San Francisco, California; 8: 410
Labianca R, Pancera G, Aitini E, et al. Folinic acid + 5-fluorouracil (5FU) versus equidose 5FU in advanced colorectal cancer. Phase III study of GISCAD (Italian Group for the Study of Digestive Tract Cancer). Ann Oncol 1991; 2: 673–9
Poon MA, O’Connel MJ, Moertel CG, et al. Biochemical modulation of fluorouracil. Evidence of significant improvement of survival and quality of life in patient with advanced colorectal carcinoma. J Clin Oncol 1989; 7: 1407–18
Doroshow JH, Multauf P, Leong L, et al. Prospective randomized comparison of fluorouracil versus fluorouracil and high dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patient previously unexposed to chemotherapy. J Clin Oncol 1990; 8: 491–501
Erlichman C, Fine S, Wong A, et al. A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 1988; 6: 469–75
Nordic Gastrointestinal Tumor Adjuvant therapy Group. Superiority of sequential methotrexate, fluorouracil and leucovorin to fluorouracil alone in advanced symptomatic colorectal carcinoma. A randomized trial. J Clin Oncol 1989; 7: 1437–46
Herrmann R, Knuth A, Kleeberg U, et al. Sequential methotrexate and 5-fluorouracil (FU) vs FU alone in metastatic colorectal cancer. Ann Oncol 1992; 3: 539–43
Machiavelli M, Leone BA, Romero A, et al. Advanced colorectal carcinoma: A prospective randomized trial of sequential methotrexate, 5-fluorouracil, and leucovorin versus 5-fluorouracil alone. Am J Clin Oncol 1991; 14: 211–7
Blijham GH, Stellestags J, Sahmoud T, et al. The modulation of high-dose 5-fluorouracil with low dose methotrexate in metastatic colorectal cancer: A phase III study of the EORTC GI Cancer Cooperative Group. Proceeedings of American Society of Clinical Oncology; 1993 May 16–18; Orlando, Florida: 12: 586
Delfino C, Caccia G, Maniago O. 5-Fluorouracil alone versus methotrexate + leucovorin + FU in patients with metastatic colorectal cancer. Proceedings of American Society of Clinical Oncology; 1992 May 17–19; San Diego; 11: 521
Abad A, Garcia P, Gravalos C, et al. Phase III trial with methotrexate, 5-FU and high-dose leucovorin vs. 5-FU, leucovorin vs. 5-FU in advanced and metastatic colorectal cancer. Proceedings of American Society of Clinical Oncology; 1993; May 16–18; Orlando, Florida; 12: 459
Cunningham D, Zalcberg J, Smith IE, et al. Tomudex: a novel thymidylate synthase inhibitor with clinical antitumor activity in a range of solid tumors. Ann Oncol 1996; 7: 179–82
Cunningham D, Zalcberg J, Rath U. et al. Tomudex: result of randomized trial in advanced colorectal cancer demonstrate efficacy and reduced mucositis and leucopenia. Eur J Cancer 1995; 31: 1945–54
Bugat R, Rougier P, Brunet P, et al. Clinical efficacy of CPT-11 in patients with inoperable advanced colorectal cancer: results of a multicentric open phase II study [abstract]. 5th International Congress of Anticancer Chemotherapy; 1995 Jan 31–Feb 3: Paris, France: S775
Pitot HC, Weder D, O’Connell MJ, et al. A phase II trial of CPT-11 (Irinotecan) in patients with metastatic colorectal carcinoma: A North Central Cancer Treatment Group (NCCTG) study [abstract]. Proceedings of American Society of Clinical of Oncology; 1994 May 14–17: Dallas, Texas; 13: 573
Shimada Y, Yashino M, Wakui A, et al. Phase II study of CPT-11, a new camptotecin derivative, in metastatic colorectal cancer. J Clin Oncol 1993; 11: 909–13
Rothenberg ML, Eckardt JR, Burric III HA, et al. Irinotecan (CPT-11) as second line therapy for pts with 5-FU refractory colorectal cancer [abstract]. Proceedings of American Society of Clinical of Oncology; 1994 May 14–17: Dallas; 13: 578
Sasaki Y, Ohtsu A, Shimada Y, et al. Simultaneous administration of CPT-11 and fluorouracil alteration of the pharmacokinetics of CPT-11 and SN-30 in patients with advanced colorectal cancer. J Natl Cancer Inst 1994; 86: 1096–8
Northover J.M, Terblanche J. A new look at the arterial supply of the bile duct in men: its surgical implication. Br J Surg 1979; 66: 379–81
Kemeny N, Seiter K, Niedzwiecki D, et al. A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone versus fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer. Cancer 1992; 69: 327–34
Kemeny N, Daly J, Reichman B, et al. Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. Ann Intern Med 1987; 107: 459
Hohn D, Stagg R, Friedman M, et al. A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group Trial. J Clin Oncol 1989; 7: 1646
Chang AE, Schneider PD, Sugarbaker. A prospective randomized trial of regional versus systemic continuous 5-Fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 1987; 206: 685
Martin JK, O’Connell MJ, Wieand HS, et al. Intra-arterial floxuridine versus systemic fluorouracil for hepatic metastases from colorectal cancer: a randomized trial. Arch Surg 1990; 125: 1022
Wagman LD, Kemeny MM, Leong L, et al. A prospective randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 1990; 8(11): 1995
Niederhuber JE. Arterial chemotherapy for metastatic colorectal cancer in the liver. Conference Advances in Regional Cancer Therapy. Gissen, West Germany, 1985
Piedbois P, Buyse M, Kemeny N, et al. Reappraisal of hepatic arterial infusion in the treatment of non resectable liver metastases from colorectal cancer. J Natl Cancer Inst 1996; 88(5): 252–8
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An erratum to this article is available at http://dx.doi.org/10.1007/BF03260139.
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Labianca, R., Pessi, M.A. & Zamparelli, G. Treatment of Colorectal Cancer. Drugs 53, 593–607 (1997). https://doi.org/10.2165/00003495-199753040-00005
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DOI: https://doi.org/10.2165/00003495-199753040-00005